Field of the Invention
The present invention concerns a method of producing complexes of long chain polyunsaturated fatty acids, their salts and esters inclusive of fish and vegetable oil glycerides, with cyclodextrins (.alpha.-, .beta.- and .gamma.-cyclodextrin and hydroxypropyl-.beta.-cyclodextrin), and the resulting complexes.
The dietetic and pharmaceutical use of fish oils and of polyunsaturated fatty acids in the form of glycerides is expanding due to their fat lowering ability (Y. Tamura et al., Prog. Lipid. Res., 25, 461, 1986; C. Von Schacky, Ann. Intern. Med., 107, 890, 1987), their platelet anticoagulant properties (C.R.M. Hay et al., Lancet, ii, 1269, 1982), and usefulness in the prevention and treatment of the most important cardiovascular diseases. Additionally, pressing evidence regarding other therapeutic uses for these materials is arising: in the treatment of psoriasis, rheumatoid arthritis (J.M. Kremer et al., Ann. Intern. Med., 106, 497, 1987; R.T. Sperling et al., Arth. Rheum., 30, 988, 1987), polyposis of the colon , arterial hypertension (K.M. Bonaa et al., N. Engl. J. Med., 322, 795, 1990; M.R. Knapp et al., N. Engl. J. Med., 320, 1037, 1989) and in the therapy of cancer.
Unfortunately, fish oils, some vegetable oils, and the polyunsaturated fatty acids that make them up, as well as certain derivatives of these materials, exhibit characteristics which markedly limit their use: they are liquid at room temperature, unctuous, and have an unpleasant taste and odour. They are easily oxidized in air owing to the large number of carbon-carbon double bonds in their molecules, and the consequent deterioration over time of organoleptic characteristics and the potential formation of epoxy groups are considered to provide toxic effects.
These characteristics markedly curtail the dietetic and pharmaceutical use of these products. For instance, dosage forms such as tablets are precluded as are hard gelatin capsules, syrups, drinking vials, and water-dispersible granules in single dose sachets.
In practice, the sole pharmaceutical form of these materials that is used is soft gelatin capsules, normally of considerable size owing to the rather high dosage typically necessary (up to several grams daily). This extra large size makes the use of the capsules by the elderly, who are the principal users owing to the pathologies mentioned above, quite difficult. These patients would have no difficulty if they were to take e.g., syrups or water dispersible granules.
In an attempt to overcome these disadvantages, U.S. Pat. No. 4 438 106 describes inclusion compounds of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), their alkaline salts and alkyl esters, in cyclodextrin, obtained by a complexation reaction occurring in the presence of large quantities of a polar organic solvent and through boiling. In the resulting complexes, the quantity of oleaginous substance is never more than 15% by weight, even under the best conditions. A 15% by weight concentration of active substance requires that frequent daily doses be administered in order to attain the pharmacologically active quantity of active ingredient; moreover, oversize dosage units must be prepared to ensure such quantities, not to mention the excessive use of the complexant cyclodextrin which is inactive per se but has a negative impact on the cost of the finished product. Moreover, the use of large quantities of organic solvents negatively influences the production costs and presents rather considerable risks to the operator (fire, explosion, intoxication by inhalation) and to the user (unavoidable traces of solvents in the finished product).